Publication: Análisis comparativo del efecto de la Validamicina A y la Anfotericina B sobre Candida albicans
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Date
2020-04-13
Authors
Guirao-Abad, José P. ; Sánchez-Fresneda Pinto, Ruth ; Argüelles ; Martínez-Esparza Alvargonzález, María Concepción
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Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Bioquímica y Biología Molecular B e Inmunología ; Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Genética y Microbiología
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Abstract
RESUMEN
La levadura dimórfica Candida albicans es el hongo patógeno oportunista con mayor prevalencia en humanos. Actualmente, los mayores problemas en la práctica clínica provienen del incremento de candidiasis sistémicas nosocomiales, la baja toxicidad selectiva de los antifúngicos disponibles y el aislamiento creciente de cepas resistentes. Todos estos datos hacen necesaria la búsqueda de nuevos blancos antifúngicos. Las rutas implicadas en el metabolismo de la trehalosa se han considerado dianas potenciales para el desarrollo de nuevos compuestos antifúngicos. La validamicina A es un inhibidor competitivo de de la actividad trehalasa y se ha aplicado con éxito para controlar el añublo de la vaina de arroz producida por el hongo fitopatógeno Rhizoctonia solani en Japón y China. Sin embargo, la acción de la validamicina A contra hongos patógenos en humanos no ha sido estudiada. Nuestros datos sugieren que bajas concentraciones de validamicina A (0,1 mg/ml) causan una pérdida parcial de la viabilidad celular en la cepa parental (CAI-4). Es necesario aplicar dosis elevadas, (1 mg/ml) de validamicina A, para lograr un grado significativo de muerte celular. El mutante congénico atc1Δ/atc1Δ carente de actividad trehalasa ácida (Atc1p) funcional fue menos sensible a la presencia de validamicina A. Además, la validamicina A actúa como un potente inhibidor competitivo de esta actividad Atc1p localizada en la pared celular así como de la trehalasa citosólica (Ntc1p). En general, la validamicina A actúa como un compuesto antifúngico débil contra Candida albicans, pero efectivo como inhibidor de trehalasas.
ABSTRACT The opportunistic dimorphic yeast Candida albicans is the most prevalent infectious fungus in humans. At present, the most dangerous problems faced in clinical practice are the dramatic increase of nosocomial bloodstream candidiasis, the low selective toxicity of available antifungal therapies and the increase resistant yeast strains. All these data make necessary the search for new antifungal targets. The pathways involved in trehalose metabolism have been proposed as potentially interesting targets for the development of new antibiotics. Validamicin A is a competitive inhibitor of trehalase activity and has been successfully applied in the fight against rice sheath blight caused by the phytopathogen fungus Rhizoctonia solani in Japan and China. However, the action of validamycin A against fungal human pathogens had never been examined so far. Our data suggest that a concentration of 0.1 mg/ml of validamycin A caused a partial loss of cell viability on the parental strain (CAI-4). Higher concentrations (1 mg/ml) of Validamycin A were required in order to achieve a significant degree of cell killing. A congenic atc1Δ/atc1Δ mutant lacking functional Atc1p activity was less sensitive to the presence of validamycin A. In addition, validamycin A acts as a potent competitive inhibitor on the cell-wall linked trehalase (Atc1p) as well as on the cytosolic trehalase (Ntc1p). Collectively, validamycin A behaves as a weak antifungal against Candida albicans, but is an effective compound as inhibitor of trehalases.
ABSTRACT The opportunistic dimorphic yeast Candida albicans is the most prevalent infectious fungus in humans. At present, the most dangerous problems faced in clinical practice are the dramatic increase of nosocomial bloodstream candidiasis, the low selective toxicity of available antifungal therapies and the increase resistant yeast strains. All these data make necessary the search for new antifungal targets. The pathways involved in trehalose metabolism have been proposed as potentially interesting targets for the development of new antibiotics. Validamicin A is a competitive inhibitor of trehalase activity and has been successfully applied in the fight against rice sheath blight caused by the phytopathogen fungus Rhizoctonia solani in Japan and China. However, the action of validamycin A against fungal human pathogens had never been examined so far. Our data suggest that a concentration of 0.1 mg/ml of validamycin A caused a partial loss of cell viability on the parental strain (CAI-4). Higher concentrations (1 mg/ml) of Validamycin A were required in order to achieve a significant degree of cell killing. A congenic atc1Δ/atc1Δ mutant lacking functional Atc1p activity was less sensitive to the presence of validamycin A. In addition, validamycin A acts as a potent competitive inhibitor on the cell-wall linked trehalase (Atc1p) as well as on the cytosolic trehalase (Ntc1p). Collectively, validamycin A behaves as a weak antifungal against Candida albicans, but is an effective compound as inhibitor of trehalases.
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